%0 Journal Article
%A Sun, Chengzao
%A Trevaskis, James L.
%A Jodka, Carolyn
M.
%A Neravetla, Swetha
%A Griffin, Pete
%A Xu, Kui
%A Wang, Yan
%A Parkes, David G.
%A Forood, Bruce
%A Ghosh, Soumitra S.
%D 2013
%T Bifunctional PEGylated Exenatide-Amylinomimetic
Hybrids
to Treat Metabolic Disorders: An Example of Long-Acting Dual Hormonal
Therapeutics
%U https://acs.figshare.com/articles/journal_contribution/Bifunctional_PEGylated_Exenatide_Amylinomimetic_Hybrids_to_Treat_Metabolic_Disorders_An_Example_of_Long_Acting_Dual_Hormonal_Therapeutics/2349352
%R 10.1021/jm401418s.s001
%2 https://acs.figshare.com/ndownloader/files/3987808
%K Compound 10
%K peptide hormones
%K vivo activities
%K glucose control
%K phybrid
%K 40 kD PEG moiety
%K Metabolic Disorders
%K DIO rats
%K efficacy
%K Hormonal TherapeuticsPeptide hybrids
%K body weight reduction
%K PEGylated
%K AC
%K 21 days
%X Peptide hybrids (phybrids) comprising
covalently linked peptide
hormones can leverage independent biological pathways for additive
or synergistic metabolic benefits. PEGylation of biologics offers
enhanced stability, duration, and reduced immunogenicity. These two
modalities can be combined to produce long-acting therapeutics with
dual pharmacology and enhanced efficacy. Compound 10 is
composed of an exenatide (AC2993) analogue, AC3174, and an amylinomimetic,
davalintide (AC2307), with an intervening 40 kD PEG moiety. It displayed
dose-dependent and prolonged efficacy for glucose control and body
weight reduction in rodents with superior in vitro and in vivo activities compared to those of a side-chain
PEGylated phybrid 6. In diet-induced obese (DIO) rats,
the weight-loss efficacy of 10 was similar to that of
a combination of PEG-parents 3 and 4. A
single dose of 10 elicited sustained body weight reduction
in DIO rats for at least 21 days. Compound 10’s
terminal half-life of ∼27 h should translate favorably to weekly
dosing in humans.
%I ACS Publications